Cancer can be considered a disease of aging due to the fact the majority of patients diagnosed are over the age of 55 years old. Immunotherapy (IT) offers perhaps the greatest likelihood for cancer control or eradication and has recently shown great promise in its application. However, it can also be associated with significant toxicities which can limit the efficacy and/or duration of treatment. Surprisingly, there has been a paucity of preclinical studies evaluating the impact of age on IT responses. We have exciting preliminary data indicating that age and body fat content has a marked and dramatic impact on inducing a pro-inflammatory state and outcome after application of IT. Aged mice rapidly succumbed to multi-organ toxicities due to induction of a cytokine storm. This inflammatory state was also exacerbated with high body fat content. Reduction in body fat composition or blockade of TNF could allow for successful IT to be applied in tumor models in the aged. Additionally, a potent immunosuppressive environment was induced following IT which markedly limits the duration and efficacy of treatment. The current proposal will seek to discern the mechanism(s) underlying these dramatic consequences and assess means to circumvent them to improve anti-tumor efficacy while minimizing toxicities. We propose 3 SPECIFIC AIMS assessing the effects and efficacy of IT in aged versus young mice: SPECIFIC AIM 1 will ascertain the role of macrophages on this heightened pro-inflammatory state as well as therapeutic intervention with cytokine blockade and/or caloric restriction. Effects on not only the cytokines but the cytokine receptors will be determined. Both human and mouse macrophages will be assessed by microarray to identify other targets which allow for successful application of IT. SPECIFIC AIM 2 will build off this aim and assess the interventions (macrophage depletion, TNF/IL6 blockade, caloric restriction) on the anti-tumor effects and immune parameters following IT. Various tumor models including the slowly progressing MINO breast cancer model will be applied. Finally, SPECIFIC AIM 3 will dissect the immunosuppressive environment induced after IT and determine if age/body fat content impacts the extent of immunosuppression induced with the hypothesis that strong immune stimulation will particularly have a long- lasting impact on the aged immune system. We will apply the anti-inflammatory approaches including use of ghrelin based on our preliminary data, to reduce these suppressive pathways and allow for greater immune augmentation in increased and durable anti-tumor effects. This proposal therefore has the potential for immediate clinical translatability and impact on human cancer patients.